Department of Medicine Division of Nephrology Helsinki University Central Hospital Helsinki, Finland and Folkhälsan Research Center Folkhälsan Institute of Genetics University of Helsinki Helsinki, Finland Arterial stiffness and cardiovascular risk factors Mats Rönnback Academic dissertation To be presented with the permission of the Medical Faculty of the University of Helsinki, for public examination in Biomedicum Helsinki, on December 21, 2007, at 12 noon. Helsinki 2007 Supervisor Per-Henrik Groop, MD, DMSc Docent Folkhälsan Research Center University of Helsinki Helsinki, Finland Reviewers Kai Metsärinne, MD, DMSc Docent Department of Medicine University of Turku Turku, Finland and Ilkka Pörsti, MD, DMSc Professor Department of Medicine University of Tampere Tampere, Finland Opponent Markku Laakso, MD, DMSc Professor Department of Medicine University of Kuopio Kuopio, Finland ISBN 978-952-92-3137-9 (paperback) ISBN 978-952-10-4434-2 (pdf) Yliopistopaino Helsinki 2007 To Ansku, Alvin, and Ebbe Contents CONTENTS........................................................................................................................4 ABSTRACT........................................................................................................................6 LIST OF ORIGINAL PUBLICATIONS............................................................................ 8 ABBREVIATIONS ............................................................................................................ 9 1. INTRODUCTION ........................................................................................................ 10 2. REVIEW OF THE LITERATURE .............................................................................. 12 2.1. Arterial stiffness..................................................................................................... 12 2.1.1. Definitions of arterial stiffness........................................................................ 12 2.1.2. The role of extracellular matrix ...................................................................... 14 2.1.3. Endothelial function........................................................................................ 15 2.1.4. Intima media thickness ................................................................................... 17 2.1.5. Methods for assessment of arterial stiffness ................................................... 18 2.1.5.1. History...................................................................................................... 18 2.1.5.2. Pulse pressure.......................................................................................... 19 2.1.5.3. Pulse wave velocity.................................................................................. 21 2.1.5.4. Pulse wave analysis ................................................................................. 22 2.1.5.5. Diastolic pulse contour analysis.............................................................. 24 2.1.5.6. Ultrasonography...................................................................................... 24 2.1.5.7. Magnetic resonance imaging................................................................... 25 2.1.5.8. Ambulatory arterial stiffness index.......................................................... 25 2.1.6. Factors that affect arterial stiffness................................................................. 26 2.1.6.1. Age ........................................................................................................... 26 2.1.6.2. Hypertension............................................................................................ 26 2.1.6.3. Physical activity and muscle fibre distribution........................................ 27 2.1.6.4. Smoking.................................................................................................... 28 2.1.6.5. Other factors ............................................................................................ 29 2.1.7. Treatment of arterial stiffness ......................................................................... 30 2.1.7.1. Pharmacological therapy......................................................................... 30 2.1.7.1.1. Vasodilator agents............................................................................. 30 2.1.7.1.2. Drugs affecting vessel wall structure................................................ 31 2.1.7.1.3. Other drugs........................................................................................ 31 2.1.7.2. Lifestyle modification............................................................................... 32 2.1.7.2.1. Sodium intake ................................................................................... 32 2.1.7.2.2. Weight loss........................................................................................ 33 2.1.7.2.3. Dietary modification ......................................................................... 33 2.2. Preeclampsia .......................................................................................................... 34 2.3. Type 1 diabetes ...................................................................................................... 35 2.4. Type 2 diabetes ...................................................................................................... 36 2.5. Milk-derived biologically active peptides ............................................................. 37 3. AIMS OF THE PRESENT STUDY............................................................................. 39 4. SUBJECTS AND STUDY DESIGN............................................................................ 40 4.1. Ethical aspects........................................................................................................ 40 4.2. Healthy men (I)...................................................................................................... 40 4.3. Women with current or previous preeclampsia (II)............................................... 40 4.4. Patients with type 1 diabetes (III) .......................................................................... 41 4.5. Control subjects (III).............................................................................................. 41 4.6. Patients with type 2 diabetes (IV).......................................................................... 42 4.7. Subjects with mild hypertension (V) ..................................................................... 42 5. METHODS ................................................................................................................... 44 5.1. Definitions.............................................................................................................. 44 5.1.1. Hypertension................................................................................................... 44 5.1.2. Preeclampsia ................................................................................................... 44 5.1.3. Diabetes........................................................................................................... 45 5.2. Blood pressure measurement ................................................................................. 45 5.3. Pulse wave velocity (I)........................................................................................... 46 5.4. Pulse wave analysis (I, II, and V) .......................................................................... 46 5.5. Endothelial function testing (I and V) ................................................................... 47 5.6. Assessment of physical activity (I)........................................................................ 48 5.7. Verification of mortality data (IV)......................................................................... 49 5.8. Assays .................................................................................................................... 49 5.9. Statistical methods ................................................................................................. 50 6. RESULTS ..................................................................................................................... 52 6.1. Study I.................................................................................................................... 52 6.2. Study II................................................................................................................... 56 6.3. Study III ................................................................................................................. 58 6.4. Study IV................................................................................................................. 66 6.5. Study V .................................................................................................................. 74 7. DISCUSSION............................................................................................................... 79 7.1. Methods.................................................................................................................. 79 7.2. Study I.................................................................................................................... 81 7.3. Study II................................................................................................................... 84 7.4. Study III ................................................................................................................